CS204029B2 - Method of producing derivatives of 3-/1-pyrazolyl/-pyridazine - Google Patents

Abstract

3-(1-Pyrazolyl)-pyridazine derivatives of the formula I, or pharmaceutically acceptable acid addition salts thereof, which decrease high blood pressure and inhibit catabolism or prostaglandins, <IMAGE> (I) wherein R1 is hydrogen or C1-4 alkyl, R2 is hydrogen, cyano, carboxyl, carbamoyl, carbaxoyl or C1-4 alkoxycarbonyl, R3 is hydrogen or chlorine or -NR4NHR5 or NR6R7, wherein R4 and R5 are each hydrogen or C1-4 alkyl, wherein R6 and R7 are each hydrogen or C1-5 alkyl, C1-5 hydroxyalkyl, C3-7 cycloalkyl, phenyl or benzyl, or benzyl or phenylethyl substituted with one or two chlorine atoms or methoxy groups, or a furylmethyl, pyridylmethyl, pyrrolidine or piperazine ring, or when R7 is hydrogen, R6 is -(CH2)n -NR4R5 wherein n is an integer from 1 to 3.

Description

The present invention provides a process for the preparation of novel 3- (1-pyrazolyl) -pyridazine derivatives as well as pharmaceutically acceptable salts thereof.

It is known that one of the most dangerous forms of hypertension is the so-called renal hypertension, resulting from renal insufficiency, characterized by both contraction of the renal blood vessels and, according to recent research, a reduced prostaglandin content in the walls of the renal blood vessels (Circ. Res. 36). 37, Supplement I., pp. 68 and 81, 1975), which is closely related to the contraction of blood vessels.

It has now been found that the novel 3- (1-pyrazolyl- [beta] -pyridazine compounds of formula I have a significant hypotensive effect and are capable of significantly inhibiting enzymes (prostaglandin dehydrogenase and progestanglandin-A-isomerase), thereby regulating the catabolism of prostaglandins, resulting in increased internal prostaglandin levels.

The process according to the invention therefore relates to the preparation of the novel 3- (1-pyrazolyl) -pyridazine derivatives of the formula I

where

R ¹ represents a hydrogen atom or a C 1 -C 4 alkyl group,

R ² is cyano, carbamoyl or alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy part,

R ³ represents a group of the formula -NR ⁴ -NHR ⁵ , wherein each of R ⁴ and R ⁵ independently of one another is hydrogen or al204029 is a keel group having 1 to 4 carbon atoms, or R 3 represents a group of formula -NR ⁶ R ⁷ , wherein R ⁶ is hydrogen and

R ⁷ represents hydroxyalkyl of 1 to 5 carbon atoms, -cycloalkyl of 3 to 7 carbon atoms, phenyl, benzyl, further benzyl or phenylethyl substituted by 1 or 2 chlorine or methoxy groups, furthermore furylmethyl, pyridylmethyl or pyrrolidinylmethyl or - (CH 2) n NR ⁴ R ⁵ in which n is 1, 2 or 3 and R 4 and R 5 are as defined above, or-NR ⁶ R 7 is a m-orpholine or piperazine residue, and pharmaceutically acceptable addition salts thereof - with acids.

In the compounds of formula I, R @ 1 is preferably hydrogen, while R @ ² can be, for example, ethoxycarbonyl, cyano or carbamoyl, and R @ 3 can be, for example, hydrazine, cyclopropylamino or benzylamino.

The compounds of the formula I according to the invention are prepared by the preparation of a compound of the formula II

R1 R ' ² \ / C = CZ \ C2H5O CN (Π) where

R ¹ has the abovementioned meaning and

R 2 represents a cyano or C 1 -C 4 alkoxycarbonyl group reacted with a 6-chloro-3-pyrldazinylhydrazine of the formula IV

CC (V) and optionally converting the cyano group of the compound of formula III thus obtained

R ¹ has the abovementioned meaning and

R 2 is cyano or C 1 -C 4 alkoxycarbonyl in the carbamoyl group by hydrolysis when R 2 is -cyano - the compound of formula III is reacted with a hydrazine of formula

R 4 NH-NHR 5 wherein

R4 and R5 are as defined above, or with an amine of formula

HNR6R7, where

R ⁶ and R ⁷ are as defined above, and optionally the free base thus obtained of formula (I) is converted into a pharmaceutically acceptable acid addition salt or the acid addition salt is converted into a free base.

In the reaction of the compounds of the formula II with the compound of the formula IV, preferably lower alcohols are used as solvents, and the reaction is preferably carried out at a temperature in the range 50 to 120 ° C. Then, the chlorine atom in the pyridazine moiety of the compound of formula (I) thus obtained is reacted with a hydrazine of formula R 7 NH-NHR 5 or with an amine of formula NH-Re R 7 wherein R 4, R 5, R 6 and R 7 are as hereinbefore defined. %, preferably at a temperature in the range of 50 to 180 ° C. Suitable solvents are polar compounds, for example dimethylformamide or dimethylsulfoxide.

Many of the compounds of formula (II) have been described in the literature (Beilsteins * Handbuch der Organischen Chemie 3, p. 470, published by Julius Springer, Berlin, 1941 and the same, I. Supplement 3, p. 162, published by J. Springer). , 1929) and can be prepared by reacting malonic nitrile or cyanoacetic acid esters with an ortho acid ester.

Of the compounds of formula III, 3-pyridazinylhydrazine and S-chloro-6-pyridazinylhydrazine are described in the literature [Yakugaku

Zasschi, 75, 778 (1955); Chem. Abstr. 59, 4970b, 1956].

The acid amides of formula (I) are conveniently obtained by partial hydrolysis of the respective nitriles, suitably with sulfuric acid, at a temperature in the range of 0 to 30 ° C.

The carboxylic acid esters of formula (I) are conveniently converted to hydrazides by using an excess of hydrazine in a lower aliphatic alcohol solvent, suitably at the boiling point of the alcoholic solvent.

The carboxylic acids of formula I are conveniently prepared by alkaline hydrolysis of the respective esters. The hydrolysis is preferably carried out with sodium hydroxide solution or where

Cl

potassium hydroxide, in a lower water-containing aliphatic alcohol at the boiling point of the solvent.

Compounds of formula I wherein R 2 is hydrogen are prepared from acids of formula I, preferably by decarboxylation by heat treatment or by simultaneous hydrolysis and decarboxylation of the respective esters with 48% hydrobromic acid, suitably at the boiling point of the reaction mixture.

Acid addition salts of compounds of formula I may conveniently be prepared as follows: The base of formula I is dissolved, for example, in methanol, ethanol, isopropanol or ether, and a solution of the inorganic acid in methanol, ethanol or ether or a solution of the appropriate organic acid in methanol, ethanol, isopropanol, ether or acetone. The precipitated product is filtered off and optionally recrystallized.

Suitable inorganic acids are hydrochloric, hydrobromic, sulfuric or phosphoric acids. Tartaric, maleic, fumaric, methanesulfonic, ethanesulfonic or 4-toluenesulfonic acids are suitable as organic acids.

The hypotensive effect of the compounds of the invention has been demonstrated in cats of both sexes of 2-4 kg, anesthetized intraperitoneally with 30 mg / kg of Pentobarbital (L.A. Geddes; Direct and Indirect Blood Pressure Measurements, edited by Year Book Medical Publishers, Chicago 1970). Test substances were administered at doses of 5, 2.5 and 1 mg / kg, using Hydralazine (1-hydrazinophthalazine hydrochloride) as a control. The hypotensive effect of several compounds is shown in Table I.

TABLE I

Ex.

Reduction of blood pressure in Pa by application of 1 mg / kg

Acute oral toxicity in mice LD50, in mg / kg

7 —1995 1000 30 -5320 200 31 —1330 250 32 —1330 200 33 —1330 -150 Hydralazine —5320 200

The hypotensive effect of the compound of Example 30 was also investigated in spontaneously hypertensive rats (Wistr-Okamoto) [Arzneim. forums. 6, p. 222 (1956)]. Systolic blood pressure is measured in the tail artery by the indirect method after oral administration. At the dose of 20 mg / kg compound of Example 30 induces a reduction in blood pressure of 31% after 2 hours and 16% after 5 hours and about _15/0 to 24 hours. Hydralazine, used as a control compound at a dose of 10 mg / kg, induces a decrease of 21, 22 and 15% after those time periods. An advantageous property of the compound of Example 30 over Hydralazine is that it does not induce any significant tachycardia.

Prostaglandin A isomerase inhibitory activity of the compounds of the present invention is measured by the method of Jones et al. [Biochim. Biophys. Acta 280, p. 558 (1972)] on a prostaglandin-A-isomerase preparation from swine plasma, whereas the prostaglandin dehydrogenase inhibitory effect is determined by the Marrazzi and Matschinsky method (prostanglandins 1, p. 373 (1973)) on prostaglandin dehydrogenase. The inhibitory effect of several compounds produced by the process of the invention against prostaglandin A isomerase and prostaglandin dehydrogenase is shown in Table II.

Ί

TABLE II o / o inhibiting amount at final concentrations expressed in millimoles prostaglandine dehydrogenase prostaglandin A isomerase

Ex.

5 0 0.10 6 0,055 0.05 11 0 0,044 16 0.16 0,075 17 0.20 0,025 18 0. 0,036 20 May 0 0.18 38 0,045 0,025 40 0 0,075 Hydralazine -. 0.09 Estron 0.01 - triiodothyroacetic acid 0.005 -

Im%, i.e. the inhibition index is defined as the concentration of the respective compound inhibiting 50% of the function of the respective enzyme.

The process according to the invention is illustrated by the following examples.

Example 1

Preparation of 3- (4-methyl-1-piperazino) -6- (4-ethoxycarbonyl-5-aminopyrazolyl) -pyridazine

A mixture of 5.36 g (20 mmol) of 3-chloro-6- (4-ethoxycarbonyl-5-amino-1-pyrazolyl) -pyridazine and 4.4 g (44 mmol) of 1-methylpiperazine is heated at 150 DEG C. for 6 hours and after cooling, the precipitated crystals were triturated with water, filtered and recrystallized from methanol to yield 4.8 g (73.5%, theory), m.p. C.

The compounds of formula (I) produced by the above process, as well as their acid addition salts, are listed in Table III.

TABLE · III

Compound ; ’Example · Chemical name of the compound T. t. Noc: 2 ° C Yield 2 3 · · bis- (hydroxyethyl) amino-6- (4-ethoxy-) 144-146 42.5 carbonyl-5-amino-1-pyrazolyl) -pyridazine 3 3-hydroxyethylamino-6- (4-ethoxycarbonyl- 191-193 76 5-amino-1-pyrazolyl) -pyridazine 168 - 170 * 4 3- (3,4-dimethoxyphenylethylamino) -6- (4- 126-127 69.5 -ethoxycarbonyl-5-amino-1-pyrazolyl) - 189 - 192 -pyridazine 5 3-Cyclohexylamino-6- (4-ethoxycarbonyl) 171-173 96 -5-81 (00-1) -pyridazine 6 3-furfurylamino-6- (4-ethoxycarbonyl-5- 161-164 52.5 (amino-1-pyrazolyl) -pyridazine 175 - 178 7 3-Benzylamino-6- (4-ethoxycarbonyl- 135-137 62.5 -5-amino-1-pyrazolyl) -pyridazine 200 - 203 * 8 3-Morpholino-6- (4-ethoxycarbonyl-5- 172-175 83 (amino-1-pyrazolyl) -pyridazine 175 - 176 9 3- (cyclopropylamino) -6- (4-ethoxycarbonyl) 167-170 64 1- (5-Aanino-1-pyrazolyl) -pyridazine 215 - 217 10 3- (4-hydroxy ^ι roxyetny 1-1-piperazino) -6- (4-etho- 141-143 73 oxycarbonyl-5-amino-1-pyrazolyl) -pyridazine 11 3- (2-diethylamino-ethynyl) -6- (4-4-etho- 108-110 62.5 oxycarbonyl-5-amino-1-pyrazolyl) -pyridazine 12 3-Phenylethylamino-6- (4-ethoxycarbonyl- 146-147 49 -5-amino-1-pyrazol-yl) -pyridazine 176 - 179 13 3- (4-Chlorobenzylamino) -6- (4-ethoxycarbone) 160-162 84.5 1- (4- (4-methyl-pyrazolyl) -pyridazine) 206 - 208 14 3-cyclonexylmethylamino-6- (4-ethoxycar- 174-176 71.5 bony 1 -amino-pyrazo-yl) -pyridazine 198 - 200

Compound ; Example no. Chemical name of the compound M.p. Yield ‘0/0 15 Dec 3-anilino-6- (4´ethoxycarbonyl-5-amino- 250-252 62 -1-pyrazolyl) -pyridazine 249 - 251 16 3- [2-pyridylmethylamino) -6- (4-ethoxycarbonyl) 155-158 52 bonyl-5-amino-1-pyrazolyl) -pyridazine 198 - 200 17 3- (3-pyrimidylmethylamino) -6- (4-ethoxycarbonyl) 163-165 72 bonyl-5-amino-1-pyrazolyl) -pyridazine 190-191 * with decomposition 18 3- (4-pyridylmethylamino) -6- (4-ethoxycar- 135-137 71 bonyl-5-amino-1-pyrazolyl) -pyridazine 165 - 168 19 Dec 3- (4-methoxybenzylamino) -6- (4-ethoxycar- 187-190 62.5 bonyl-5-amino-1-pyrazolyl) -pyridazine 207 - 210 20 May 3- (1-phenylethylamino) -6- (4-ethoxycarbo- 159-160 30.5 nyl-5-amino-pyrazolyl) -pyridazine 209 - 212 ' 21 3- (1-Ethyl-2-pyrrolidinyl-methylamino) -6- 192-195 68

- (4-ethoxycarbonyl-5-amino-1-pyrazolyl) -pyridazine *: hydrochloride **: preparation yield (after recrystallization)

Example 22

Preparation of 3- (4-ethoxycarbonyl-5-amino-1-pyrazolyl) -pyridazine as described in Example 22. Yield 85.5%, mp 193-194 ° C.

Example 24

A mixture of 48.4 g (0.44 mole) of 3-pyridazinylhydrazine, 75 g (0.444 mole) of ethyl-ethoxymethylenocyanoacetate and 500 ml of ethanol is refluxed for 3 hours. Yield: 62.7 g (59.5% of theory), m.p. 126 DEG-129 DEG.

Example 23

Preparation of 3-chloro-6- (4-methoxycarbonyl-5-amino-1-pyrazolyl) -pyridazine

This compound is obtained by the following procedure: Preparation of 3-chloro-6- (4-cyano-5-amino-1-pyrazolyl) -pyridazine

A mixture of 3.35 g (30 mmol) of 3-chloro-6-pyridazinylhydrazine, 3.96 g (30 mmol) of ethoxymethylenemalonitrile and 60 ml of ethanol was heated at reflux for 2 hours. After cooling, the precipitated crystals are filtered off, washed with ethanol and dried. Yield 5.85 g (88.5% of theory), mp 250-252 ° C.

The compounds of formula (I), prepared as described above, are listed in Table IV.

TABLE IV

The compound of Example no.

Chemical name of the compound

M.p. Yield * ° C%

25 3- (4-cyano-5-amino-1-pyrazolyl) -pyridazine 250-251 60 26 3- (3-Methyl-4-cyano-5-amino-1-pyrazolyl) -pyridazine 239 - 241 31 27 Mar: 3-Chloro-6- (3-methyl-4-cyano-5-) 296 - 299 77.5

(amino-1-pyrazolyl) -pyridazine *: Preparation yield (after recrystallization) is triturated with 15 ml of hot ethanol, then filtered and dried. Yield 3.05 g (93.5% of theory), m.p.

Example 29

Preparation of 3- (4-carbamoyl-5-amino-1-pyrazolyl) -pyridazine

This compound is prepared by

Example 28

Preparation of 3-chloro-6- (4-carbamoyl-5-amino-1-pyrazolyl) pyridazine

A mixture of 3 g of 3-chloro-6- (4-cyano-5-amino-1-pyrazolyl) -pyridazine, prepared as described in Example 24, and 10.5 ml of concentrated sulfuric acid is stirred at room temperature for 1 hour. The mixture is poured onto ice, the precipitate formed is filtered off, washed with water and as described in the example. 28. Yield 65.5%, mp 295-298 ° C.

Example 1 a d 3 O

Preparation of 3-hydrazino-6- (4-cyano-5-amino-1-pyrazolyl) -pyridazine

A mixture of 10 g of 3-chloro-6- (4-cyano-5-amino-1-pyyrisolyl) -pyridazine, prepared as described in Example 24, 20 ml of dimethylformamide and 40 ml of 98% hydrazine hydrate is heated at 90-95 ° C. After cooling, the precipitated product is filtered off, washed with water and ethanol, triturated with 50 ml of hot ethanol, filtered and dried, yield 9.1 g (93% of theory), m.p. mp 253-256 ° C.

The compounds of formula (I) prepared by the above process and their acid addition salts are listed in Table V.

TABLE V

The compound of Example no. Chemical name of the compound T. t. Noc: 2 ° C Yield % 31 3-Hydrazino-6- (4-ethoxycarbonyl-5-amino-1-pyrazolyl) -pyridazine 190-192 96 32 3-Hydrazino-6- (3-methyl-4-cyano- 252-255 78.5 -5-amino-1-pyrazolyl) -pyridazine 284 - 286 33 3-hydrazino-6- (4-carbamoyl-5-amino- 248-250 37.5 N-1-pyrazolyl) -pyridazine 262 - 265

*: hydrochloride **: preparation yield (after recrystallization)

Example 3 4

Preparation of 3- (1-methyl-hydrazino) -6- (4-cyano-5-amino-1-pyrazolyl) -pyridazine

A mixture of 2.2 g (10 mmol) of 3-chloro-6- (4-cyano-5-amino-1-pyrazolyl) -pyridazine, prepared as described in Example 24, 1.38 g (30 mmol) of methylhydrazine and 25 ml of dimethylformamide, was added. heated at 120-130 ° C for 7.5 hours; po ·. cooling, the mixture is poured onto ice. The precipitated crystals are filtered off, washed with water and triturated with 5 ml of hot ethanol, then filtered and dried. Yield: 2.1 g (91% of theory), m.p. 260 DEG C. (dec.).

Example 35

-6- (4-carbazoyl-5-amino-1-pyrazolinyl) -pyridazine

A mixture of 6.72 g (20 mmol) of 3- [bis- (hydroxyethyl) -amino) -6- (4-ethoxycarbonyl-5-amino-1-pyra) - [(4] [1,4] -pyridazine), prepared according to of Example 2, 34 ml of 72% hydrazine hydrate and 34 ml of dioxane are stirred at the boiling point of the mixture for 12 hours After cooling, the precipitated crystals are filtered off, washed with water and ethanol and then recrystallized from 30 ml of ethanol. (5% of theory), mp 217-219 ° C.

The compounds of formula (I) prepared as described above and their addition salts are listed in Table VI.

Preparation of 3- [bis- (2-hydroxyethyl) -amino] TABLE VI

The compound of Example no. Chemical name of the compound Mp ° C Yield % 36 3- (4-Carbazoyl-5-amino-1-pyrazolyl) -pyridazine 254-256 89 37 3- (3,4-Dimethoxyphenylethylamino) -6- (4-carbazoyl-5-amino-1-pyrazolyl) -pyridazine 195-198 54 38 3-benzylamino-6- ^{(4-carbamoyl,} benzoyl-5-amino-1-pyr azolyl) -pyridazine and 175-178 76.5 39 3- (3-pyridylmethylamino) -6- (4-carbo- 221-222 58.5 zoyl-5-amino-1-pyrazolyl) pyridazine 258 - 260 40 hydrochloride 3- (2-Furylmethylamino) -6- (4-carbazoyl-5-amino-1-pyrazolyl) -pyridazine 214-215 212 - 214 *** 87

* yields in the preparation (after recrystallization) ···: dlhydrochloride

Example 41

Preparation of 3-hydrazino-6- (4-carbazoyl-5-amino-1-pyrazolyl) -pyridazine

A mixture of 3 g of 3-chloro-6- (4-ethoxycarbonyl-5-amino-1-pyrazolyl) -pyridazine, 30 ml of 72% hydrazine hydrate and 40 ml of dioxane is stirred at the boiling point of the mixture for 24 hours. After cooling, the precipitated crystals are filtered, washed with water and ethanol, triturated with hot ethanol, filtered and dried. Yield 2.0 g (77% of theory), m.p. 302 DEG-305 DEG.

Example 42

Preparation of 3- (4-carboxy-5-amino-1-pyrazolyl) -pyridazine

A mixture of 4.43 g (19.1 mmol) of 3- (4-ethoxycarbonyl-5-amino-1-pyrazolyl) -pyridazine prepared according to Example 22 and 55 ml of an aqueous solution containing 2.28 g (57 mmol) of hydroxide The mixture was stirred at 90-95 ° C for 15 minutes, then neutralized with acetic acid and left in the refrigerator overnight. The precipitated product is filtered off, washed with water and dried. Yield 3.15 g (81% of theory), m.p. 206 DEG-209 DEG.

Example 43

Preparation of 3 * - (5-amino-1-pyrazolyl) -pyridazine

1.6 g of 3- (4-carboxy-5-amino-1-pyrazolyl) pyridazine, prepared according to Example 42, was heated at 250 ° C for 25 minutes, after cooling the precipitated product was filtered off and recrystallized from ethanol. Yield 0.8 g (64% of theory), m.p. 132-135 cc.

Example 44

Preparation of 3-cyclohexylamino-6- (5-amino-1-pyrazolyl) -pyridazine hydrobromide

A mixture of 3.3 g (10 mmol) of 3-cyclohexylamino-6- (4-ethoxycarbonyl-5-amino-1-pyrazolyl) -pyridazine prepared according to Example 5 and 25 ml of 48% hydrobromic acid is stirred at 90 ° C. to 95 ° C until gas evolution ceased (approximately 5 hours).

After cooling, the product was filtered, washed with water and recrystallized from ethanol. Yield 0.8 g (23.5% of theory), m.p. 229-232 ° C.

Example 45

Tablets, each containing 200 mg of active ingredient, for oral administration and therapeutic use are prepared from the following ingredients:

3-iidrazmo-6- (4-cyano-5-amino-1-pyrazolyl) pyridazine 200 mg microcrystalline-cellulose 146.4mg colloidal silicon dioxide 1.8mg magnesium stearate 1.8mg

The average weight of one tablet is 350 mg. The tablets are film-coated.

Preparation of the injection product

For parenteral use, a sterile freeze-dried product containing 25 mg of 3-hydrazino-6- (4-cyano-5-amino-1-pyrazolyl) -pyridazine hydrochloride in each ampoule is prepared from a solution of the compound in distilled water. for injection.

To prepare the hydrochlorides of the compounds described in the Examples, the base is suspended in ether or ethanol and saturated with hydrogen chloride gas. In some cases, it is sufficient to add an ethanolic solution of hydrogen chloride - to a suspension of the base in ether or ethanol. The precipitate formed is filtered off, washed with ether and dried. The melting points of the hydrochlorides thus obtained are included in the above tables.

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of 3- (1-pyrazolyl) -pyridazine derivatives of the general formula I wherein R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group, R2 is cyano, carbamoyl or C1-C4alkoxycarbonyl in the alkoxy moiety, R3 represents a group of formula -NR4-NHR 5 in which each of R4 and ^R5 represents independently from each other hydrogen or alkyl having 1 to 4 carbon atoms, or R ³ represents a group of formula -NR6R7 wherein R6 is hydrogen and R ⁷ is C 1 -C 5 hydroxyalkyl, C 3 -C 7 cycloalkyl, phenyl, benzyl, benzyl or phenylethyl substituted by 1 or 2 chlorine or methoxy, furylmethyl, pyridylmethyl or pyrrolidinylmethyl or formulas - (CH 2) _n NR ⁴ R ⁵ in which n is 1, 2 or 3 and R ⁴ and R ⁶ are as defined above, or -NR ⁶ R ⁷ is a morpholine or piperazine residue, and pharmaceutically acceptable salts thereof, characterized by: by treating the compound of formula II R ¹ R'2 \ / C = C / C 2 H 5 O CN (П), where R ¹ has the abovementioned meaning, and R * ² represents a cyano or alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety, reacted with a 6-chloro-3-pyrldazinylhydrazine of formula IV (IV), and R ¹ has the abovementioned meaning, and R * ² is cyano or C 1 -C 4 alkoxycarbonyl, in the carbamoyl hydrolysis group when R ^<2 is cyano - the compound of formula III is reacted with a hydrazine of formula R ⁴ NH-NHR ⁵ wherein R ⁴ and R ® are as defined above, or with an amine of formula HNR & R ⁷ , where R ⁶ and R ⁷ are as defined above, and optionally the free base of formula I thus obtained is converted into a pharmaceutically acceptable acid addition salt or the acid addition salt is converted into the free base.